KR100428703B1 - The new macrolide compounds as a helicobactoer pylori inhibitor - Google Patents

The new macrolide compounds as a helicobactoer pylori inhibitor Download PDF

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KR100428703B1
KR100428703B1 KR10-2000-0005140A KR20000005140A KR100428703B1 KR 100428703 B1 KR100428703 B1 KR 100428703B1 KR 20000005140 A KR20000005140 A KR 20000005140A KR 100428703 B1 KR100428703 B1 KR 100428703B1
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methoxy
yloxy
pyran
tetrahydro
ethyl
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김중협
김성훈
남길수
서재홍
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한국과학기술연구원
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Abstract

본 발명은 하기 화학식 1로 표시되는 화합물 및 그의 염으로서, 상기 화합물은 활동성 만성위염의 중요인자이며, 십이지장궤양의 병인론 및 위암발생에 있어 중요한 역할을 하는 헬리코박터 파이로리(Helicobactoer pylori)의 성장억제 효과가 우수하며, 다른 공지의 마크로라이드 유도체와 비교할 때 위액에 의한 분해정도가 현저하게 낮은 특징이 있다.The present invention is a compound represented by the following formula (1) and salts thereof, the compound is an important factor of active chronic gastritis, the growth inhibitory effect of Helicobactoer pylori ( Helicobactoer pylori ) plays an important role in the pathogenesis of duodenal ulcer and gastric cancer It is excellent and is characterized by a significantly lower degree of decomposition by gastric juice compared to other known macrolide derivatives.

상기 화학식 1에서, R1은 4-메톡시페녹시메틸기, 2-메톡시페녹시메틸기 또는 메톡시에톡시메틸기를 나타내고; R2는 수소원자, 아실기, 또는 저급알콕시기를 나타내고; R3는 수소원자 또는 아실기이고 각각은 모두 같거나 다르며; Q와 W는 함께 옥소를 형성하거나, Q 및 W 중 하나는 -OR4이고 다른 하나는 수소이고, R4는 수소원자 또는이며, 여기서 R3의 정의는 전술한 바와 같다.In Formula 1, R 1 represents a 4-methoxyphenoxymethyl group, 2-methoxyphenoxymethyl group, or methoxyethoxymethyl group; R 2 represents a hydrogen atom, an acyl group, or a lower alkoxy group; R 3 is a hydrogen atom or an acyl group and each is the same or different; Q and W together form oxo, or one of Q and W is -OR 4 and the other is hydrogen, and R 4 is a hydrogen atom or Wherein R 3 is as defined above.

Description

헬리코박터 파이로리의 성장 억제 효과를 지닌 신규 마크로라이드 화합물 {THE NEW MACROLIDE COMPOUNDS AS A HELICOBACTOER PYLORI INHIBITOR}New macrolide compound with growth inhibition effect of Helicobacter pylori {THE NEW MACROLIDE COMPOUNDS AS A HELICOBACTOER PYLORI INHIBITOR}

본 발명은 헬리코박터 파이로리에 대해 성장 저해효과를 갖는 신규 마크로라이드 화합물에 관한 것이다.The present invention relates to a novel macrolide compound having a growth inhibitory effect on Helicobacter pylori.

헬리코박터 파이로리(Helicobactoer pylori)는 여러 위장질환, 예를 들면, 만성위염, 위궤양, 십이지장궤양, 위암발생에 있어 중요한 원인균으로 알려져 있다. 이 헬리코박터 파이로리에 대한 성장 저해제의 개발은 의약 분야에서 중요한 관심사로 등장하였으며, 여러 에리트로마이신 유도체가 헬리코박터 파이로리에 대한 저해제로 사용될 수 있음이 공지되어 있다.Helicobacter pylori (Helicobactoer pylori) has several gastrointestinal disorders, for example, in chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer is known as an important pathogen. The development of growth inhibitors for Helicobacter pylori has emerged as an important concern in the medical field, and it is known that various erythromycin derivatives can be used as inhibitors for Helicobacter pylori.

그러나, 공지의 에리트로마이신 유도체는 성장 저해효과가 낮을 뿐 아니라, 위산에 대한 분해 정도가 높다는 단점이 있다.However, known erythromycin derivatives not only have low growth inhibitory effect, but also have a high degree of degradation of gastric acid.

따라서 본 발명은 상기 문제점을 해결하기 위해 안출된 것으로서, 헬리코박터 파이로리에 대한 성장 저해효과가 뛰어나며, 위산에 의해 쉽게 분해되지 않는 화합물을 제공하는 것을 그 목적으로 한다.Accordingly, an object of the present invention is to provide a compound having excellent growth inhibitory effect on Helicobacter pylori, which is not easily degraded by gastric acid.

본 발명자들은 헬리코박터 파이로리의 성장을 억제할 수 있는 하기 화학식 1로 표시되는 화합물을 합성하는 데 성공하였다.The present inventors have succeeded in synthesizing a compound represented by the following formula (1) capable of inhibiting the growth of Helicobacter pylori.

[화학식 1][Formula 1]

상기 화학식 1에서, R1은 4-메톡시페녹시메틸기, 2-메톡시페녹시메틸기 또는 메톡시에톡시메틸기를 나타내고; R2는 수소원자, 아실기, 또는 저급알콕시기를 나타내고; R3는 수소원자 또는 아실기이고 각각은 모두 같거나 다르며; Q와 W는 함께 옥소를 형성하거나, Q 및 W 중 하나는 -OR4이고 다른 하나는 수소이고, R4는 수소원자 또는이며, 여기서 R3의 정의는 전술한 바와 같다.In Formula 1, R 1 represents a 4-methoxyphenoxymethyl group, 2-methoxyphenoxymethyl group, or methoxyethoxymethyl group; R 2 represents a hydrogen atom, an acyl group, or a lower alkoxy group; R 3 is a hydrogen atom or an acyl group and each is the same or different; Q and W together form oxo, or one of Q and W is -OR 4 and the other is hydrogen, and R 4 is a hydrogen atom or Wherein R 3 is as defined above.

상기 화학식 1을 갖는 화합물의 제조방법은 에리트로마이신을 출발물질로 하여 공지의 방법(① J. Med. Chem., 41(21), 4080∼4100, 1998 및 ② Tetrahedron 53(34), 11753~11766, 1997) 및 이를 응용하여 합성하였으며, 특히 화학식 1중 R1은 Tetrahedron Letters 22, 1973~1976, 1981을 참고로 하여 제조하였다. 구체적인 반응 스킴은 아래의 반응식 1 및 2와 같다.Method for preparing a compound having the formula (1) is a known method using the erythromycin as a starting material (① J. Med. Chem., 41 (21), 4080-4100, 1998 and ② Tetrahedron 53 (34), 11753 ~ 11766 , 1997) and the application thereof, in particular, R 1 in Formula 1 was prepared with reference to Tetrahedron Letters 22, 1973-1976, 1981. Specific reaction schemes are shown in Schemes 1 and 2 below.

각 화합물들을 구체적으로 설명하면,When describing each compound in detail,

(1) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](1) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5 -Hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(2) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](2) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4 -(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane- 2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(3) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](3) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5 -Hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(4) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](4) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4 -(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane- 2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(5) 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](5) 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5 -Trimethylsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(6) 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](6) 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5 -Trimethelsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane-2, 10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(7) 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](7) 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4 -(5-Trimethylsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane- 2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(8) 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](8) 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-trihydroxy-4 -(5-Trimethelsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane -2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(9) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](9) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy -3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(10) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](10) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy -3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(11)아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(4-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르(11) Acetic acid 4-dimethylamino-2- [14-ethyl-4,12,12-trihydroxy-7-methoxy-10 (4-methoxyphenoxymethoxyimino) -3,5,7 , 9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl-ester

(12)아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(2-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르(12) Acetic acid 4-dimethylamino-2- [14-ethyl-4,12,12-trihydroxy-7-methoxy-10 (2-methoxyphenoxymethoxyimino) -3,5,7 , 9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl-ester

(13) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(4-메톡시-페녹시메틸)-옥심](13) 6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy -3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(14) 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(2-메톡시-페녹시메틸)-옥심](14) 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy -3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(15) 6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](15) 6- (4-dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5 Acetoxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (4-methoxy-phenoxymethyl) -oxime]

(16) 6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](16) 6- (4-dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5 Acetoxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (2-methoxy-phenoxymethyl) -oxime]

(17) 아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(4-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르(17) acetic acid 4-dimethylamino-2- [14-ethyl-4,7,12,13-tetrahydroxy-10- (4-methoxy-phenoxymethoxyimino) -3,5,7, 9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl ester

(18) 아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(2-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르(18) acetic acid 4-dimethylamino-2- [14-ethyl-4,7,12,13-tetrahydroxy-10- (2-methoxy-phenoxymethoxyimino) -3,5,7, 9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl ester

(19)13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸-3,9-다이온-9-[O-(4-메톡시-페녹시메틸)]-옥심(19) 13- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6, 8,10,12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecane-3,9-dione-9- [O- (4-methoxy-phenoxymethyl) ] -Oxime

(20)13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸3,9-다이온-9-[O-(2-메톡시-페녹시메틸)-옥심] 등이다.(20) 13- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6, 8,10,12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecane 3,9-dione-9- [O- (2-methoxy-phenoxymethyl)- Oxime].

각 화합물들의 구조는 2D 핵자기공명 분광기 및 질량분광 광도계, 적외선 분광법등을 이용하여 확인하였고, 그 순도는 고성능 액체크로마토그래피를 이용하여 결정하였다.The structure of each compound was confirmed by using 2D nuclear magnetic resonance spectroscopy, mass spectrophotometer, infrared spectroscopy, and the purity was determined using high performance liquid chromatography.

상기 화학식 1의 화합물은 헬리코박터 파이로리(Helicobactoer pylori)에 대해 성장억제 효과를 가진다. 그 결과를 표 1에 나타내었다.The compound of Formula 1 has a growth inhibitory effect on Helicobacter pylori ( Helicobactoer pylori ). The results are shown in Table 1.

헬리코박터 파이로리(Helicobactoer pylori) 최소성장억제농도Helicobacter pylori (Helicobactoer pylori) Minimum growth inhibitory concentration 화합물compound MICs (ng/ml)MICs (ng / ml) 실시예 1Example 1 3030 실시예 2Example 2 2020 실시예 7Example 7 3030 실시예 8Example 8 2020 실시예 13Example 13 4040 실시예 14Example 14 2020 클라리트로마이신(Clarithromycin)Clarithromycin 2020

상기 표 1에서 헬리코박터 파이로리(Helicobactoer pylori)의 성장억제 효과는 최저억제농도(MIC)를 아가 희석법으로 측정하였고, 헬리코박터 파이로리는 서울대학교 병원에서 얻어진 임상균주(NCTC10638)를 이용하였다. 대조약물로서는 클라리트로마이신을 사용하였다.In Table 1, the growth inhibition effect of Helicobactoer pylori (MIC) was measured by agar dilution method, and Helicobacter pylori was used for clinical strain (NCTC10638) obtained from Seoul National University Hospital. As clarithromycin, clarithromycin was used.

이하 실시예에 의하여 본 발명을 보다 구체적으로 설명하고자 한다.Hereinafter, the present invention will be described in more detail with reference to the following examples.

[실시예]EXAMPLE

실시예 1Example 1

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](3)의 제조.6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-hydroxy -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Preparation of 10- [O- (2-methoxy-phenoxymethyl) -oxime] (3).

(방법 1)(Method 1)

에리트로마이신 수화물(1 g, 1.39 mmol)을 메탄올 25ml에 녹이고, 이 용액에 합성된 구아이아콜릴메틸히드록실아민 염산염 (559 mg, 2.72 mmol)과트리에틸아민(227 ㎕,1.63 mmol)을 넣고 45℃에서 18시간 동안 가열 반응시켰다. 이 반응 혼합물을 상온으로 냉각시킨후 메틸렌 클로라이드(25 ml x 3)로 추출하였다. 유기층을 5% NaHCO3수용액 과 포화소금물로 세척하고, MgSO4로 건조시킨 후 여과하였다. 여액을 감압 농축시킨 후 실리카겔 컬럼으로 정제하였다. 용출액은 메틸렌클로라이드/메탄올/암모니아수(100/10/2)를 사용하였다.Erythromycin hydrate (1 g, 1.39 mmol) was dissolved in 25 ml of methanol and synthesized in this solution, guacolylmethylhydroxylamine hydrochloride. (559 mg, 2.72 mmol) and triethylamine (227 μl, 1.63 mmol) were added thereto, and the resulting mixture was heated at 45 ° C. for 18 hours. The reaction mixture was cooled to room temperature and extracted with methylene chloride (25 ml x 3). 5% NaHCO organic layer3Washed with aqueous solution and saturated brine, MgSO4Dried over and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column. As the eluate, methylene chloride / methanol / ammonia water (100/10/2) was used.

해당 부분을 농축시킨 후 진공건조시켜 흰색 거품형태의 고체를 얻었다.The part was concentrated and dried in vacuo to give a white foamy solid.

수율: 780 mg(65%)Yield: 780 mg (65%)

TLC: Rf=0.55(CH2Cl2/MeOH/c-NH4OH=100/10/2)TLC: R f = 0.55 (CH 2 Cl 2 / MeOH / c-NH 4 OH = 100/10/2)

FAB-MS : M+1= 886FAB-MS: M +1 = 886

1H-NMR(CDCl3, 300 MHz) δ 0.79(t, J=7.28 Hz, 3H, 15-CH3), 0.90(d, J=6.90 Hz, 3H, 19-CH3), 0.99~1.24(m, 27H), 1.32~1.49(m, 6H), 1.89~2.00(m, 2H), 2.22(s, 6H, N(CH3)2), 2.55(dd, J=13.6 Hz, 6.88 Hz, 1H, 4'-CH), 2.80~2.93(m, 2H), 3.15(dd, J=10.1 Hz, 7.3 Hz, 1H, 2'CH), 3.24(s, 3H, 3'-OCH3), 3.40(d, J=7.42 Hz, 1H, 5-CH), 3.58(m, 1H), 3.70(s, 1H, 11-CH), 3.81(s, 1H, ph-OCH3), 3.95(m, 2H, 5',3-CH), 4.32(d, J=7.22 Hz, 1H, 1'-CH), 4.89(d, J=7.5 Hz, 1'-CH), 5.15(dd, J=10.8 Hz, 1.59 Hz, 13-CH2), 5.55(d, J=7.08 Hz, 1H), 5.66(d, J=7.08 Hz, 1H), 6.82(m, 3H), 6.93(m, 2H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.79 (t, J = 7.28 Hz, 3H, 15-CH 3 ), 0.90 (d, J = 6.90 Hz, 3H, 19-CH 3 ), 0.99-1.24 ( m, 27H), 1.32-1.49 (m, 6H), 1.89-2.00 (m, 2H), 2.22 (s, 6H, N (CH 3 ) 2 ), 2.55 (dd, J = 13.6 Hz, 6.88 Hz, 1H , 4'-CH), 2.80-2.93 (m, 2H), 3.15 (dd, J = 10.1 Hz, 7.3 Hz, 1H, 2'CH), 3.24 (s, 3H, 3'-OCH 3 ), 3.40 ( d, J = 7.42 Hz, 1H, 5-CH), 3.58 (m, 1H), 3.70 (s, 1H, 11-CH), 3.81 (s, 1H, ph-OCH 3 ), 3.95 (m, 2H, 5 ', 3-CH), 4.32 (d, J = 7.22 Hz, 1H, 1'-CH), 4.89 (d, J = 7.5 Hz, 1'-CH), 5.15 (dd, J = 10.8 Hz, 1.59 Hz, 13-CH 2 ), 5.55 (d, J = 7.08 Hz, 1H), 5.66 (d, J = 7.08 Hz, 1H), 6.82 (m, 3H), 6.93 (m, 2H).

13C-nmr(CDCl3, 75.5 MHz) δ: 9.07, 10.64, 14.58, 16.05, 16.21, 18.50, 18.60, 21.20, 21.35, 21.47, 26.64, 26.95, 28.81, 33.17, 34.99, 36.42, 37.38, 39.04, 40.25, 44.69, 49.44, 55.76, 56.01, 65.42, 65.49, 68.69, 69.97, 70.93, 72.66, 74.23, 74.74, 76.74, 78.00, 79.83, 83.33, 95.67, 96.18, 102.91, 111.30, 112.64, 118.66, 120.79, 121.03, 123.51, 145.52, 150.67, 173.45, 175.28. 13 C-nmr (CDCl 3 , 75.5 MHz) δ: 9.07, 10.64, 14.58, 16.05, 16.21, 18.50, 18.60, 21.20, 21.35, 21.47, 26.64, 26.95, 28.81, 33.17, 34.99, 36.42, 37.38, 39.04, 40.25 , 44.69, 49.44, 55.76, 56.01, 65.42, 65.49, 68.69, 69.97, 70.93, 72.66, 74.23, 74.74, 76.74, 78.00, 79.83, 83.33, 95.67, 96.18, 102.91, 111.30, 112.64, 118.66, 120.79, 121.03, 121.03 , 145.52, 150.67, 173.45, 175.28.

IR(KBr, cm-1) 3485, 2976, 2937, 2867, 1725, 1501, 1471, 1372, 1337, 1267, 1167, 1057, 1018, 953, 768.IR (KBr, cm −1 ) 3485, 2976, 2937, 2867, 1725, 1501, 1471, 1372, 1337, 1267, 1167, 1057, 1018, 953, 768.

(방법 2)(Method 2)

에리트로마이신 9-옥심 20 g(26.7 mmol)을 DMF 100 ml에 녹이고 KOH 10.4 g(32.0 mmol)을 넣고 30분 동안 교반하였다. 합성한 구아이아콜릴메틸클로라이드 5 ml(29.3 mmol)를 적가하고, 5시간 동안 가열 환류한 후 구아이아콜릴메틸클로라이드 0.5 ml(2.93mmol)을 더 첨가하고 1시간 동안 반응시켰다. 반응 혼합물을 K2CO360 ml, 소금물 200 ml로 세척하고, 여과하였다. 여액을 감압 농축시킨 후, 얻어진 노란색 액체를 실리카겔 컬럼하여 분리하였다.20 g (26.7 mmol) of erythromycin 9-oxime was dissolved in 100 ml of DMF, and 10.4 g (32.0 mmol) of KOH was added thereto, followed by stirring for 30 minutes. Synthesized Guacolyl Methyl Chloride 5 ml (29.3 mmol) was added dropwise, and the mixture was heated to reflux for 5 hours, followed by further addition of 0.5 ml (2.93 mmol) of guiacolylmethyl chloride and reacted for 1 hour. K reaction mixture2CO3Washed with 60 ml, 200 ml brine and filtered. The filtrate was concentrated under reduced pressure, and the obtained yellow liquid was separated by silica gel column.

수율 : 13.2 g(55%)Yield: 13.2 g (55%)

실시예 2Example 2

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](1)의 제조.6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-hydroxy -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Preparation of 10- [O- (4-methoxy-phenoxymethyl) -oxime] (1).

에리트로마이신 9-옥심(5 g, 6.67 mmol)을 DMF 30 ml에 녹이고 얼음조를 이용하여 -5℃로 낮춘 후, KOH(550 mg, 9.9 mmol), K2CO3(910 mg, 6.6 mmol)를 한번에 가하고, 이 용액에 p-아니실메틸클로라이드(1.37 g, 8.0 mmol)을 CH2Cl210 ml에 희석시킨 용액을 적가하고, 같은 온도를 유지하며 2시간 동안 반응시켰다. 이 반응 혼합물을 에틸 아세테이트(50 ml x 3)로 추출하고, 유기층을 포화 소금물로 세척하고, MgSO4로 건조 시켰다. 건조제 여과해내고 여액을 농축한 후 실리카겔 컬럼으로 정제하였다.Erythromycin 9-oxime (5 g, 6.67 mmol) was dissolved in 30 ml of DMF and lowered to -5 ° C using an ice bath, followed by KOH (550 mg, 9.9 mmol), K 2 CO 3 (910 mg, 6.6 mmol). Was added at once, and a solution of p-anisylmethylchloride (1.37 g, 8.0 mmol) diluted in 10 ml of CH 2 Cl 2 was added dropwise and reacted for 2 hours while maintaining the same temperature. The reaction mixture was extracted with ethyl acetate (50 ml x 3) and the organic layer was washed with saturated brine and dried over MgSO 4 . Desiccant was filtered off and the filtrate was concentrated and purified by silica gel column.

수율 : 2.31 g(43%)Yield: 2.31 g (43%)

TLC: Rf=0.55(CH2Cl2/MeOH/c-NH4OH=100/10/1)TLC: R f = 0.55 (CH 2 Cl 2 / MeOH / c-NH 4 OH = 100/10/1)

FAB-MS : M+1= 886FAB-MS: M +1 = 886

1H-NMR(CDCl3, 300MHz) δ; 0.84(t, J=7.24 Hz, 3H, 15-CH3), 0.97(d, J=6.88 Hz, 3H, 19-CH3), 1.07~1.27(m, 25Hz), 1.34(s, 3H, 18-CH3), 1.55(m, 5H), 1.99(m, 2H), 2.77(s, 6H, N(CH3)2), 2.34(m, 2H, 2'-Hax), 2.65(dd, J=13.6 Hz, 6.48 Hz, 1H, 4'-H), 2.88(m, 1H, 3'-H), 3.01(t, J=9.14 Hz, 1H), 7.3(s, 1H), 3.21(dd,J=10.1 Hz, 7.3 Hz, 1H, 2'-H), 3.31(s, 3H, 3'-OCH3), 3.40~3.50(m, 2H, 5-H, 8,-H), 3.62(m, 1H, 5'-H), 3.77(s, 3H), 3.98(m, 2H, 5'-H, 3-H), 4.25(s, 1H, 11-H), 4.37(d, J=7.21Hz, 1'-H), 4.89(d, J=7.50 Hz, 1'-H), 5.15(dd, J=10.8 Hz, 1.59 Hz, 13-CH2), 5.52(dd, J=27.9 Hz, 7.19 Hz, ph-OCH2O), 6.83(m, 3H), 6.95(m, 2H). 1 H-NMR (CDCl 3 , 300 MHz) δ; 0.84 (t, J = 7.24 Hz, 3H, 15-CH 3 ), 0.97 (d, J = 6.88 Hz, 3H, 19-CH 3 ), 1.07 to 1.27 (m, 25 Hz), 1.34 (s, 3H, 18 -CH 3 ), 1.55 (m, 5H), 1.99 (m, 2H), 2.77 (s, 6H, N (CH 3 ) 2 ), 2.34 (m, 2H, 2'-Hax), 2.65 (dd, J = 13.6 Hz, 6.48 Hz, 1H, 4'-H), 2.88 (m, 1H, 3'-H), 3.01 (t, J = 9.14 Hz, 1H), 7.3 (s, 1H), 3.21 (dd, J = 10.1 Hz, 7.3 Hz, 1H, 2'-H), 3.31 (s, 3H, 3'-OCH 3 ), 3.40-3.50 (m, 2H, 5-H, 8, -H), 3.62 (m , 1H, 5'-H), 3.77 (s, 3H), 3.98 (m, 2H, 5'-H, 3-H), 4.25 (s, 1H, 11-H), 4.37 (d, J = 7.21 Hz, 1'-H), 4.89 (d, J = 7.50 Hz, 1'-H), 5.15 (dd, J = 10.8 Hz, 1.59 Hz, 13-CH 2 ), 5.52 (dd, J = 27.9 Hz, 7.19 Hz, ph-OCH 2 O), 6.83 (m, 3H), 6.95 (m, 2H).

13C-nmr(CDCl3, 75.5 MHz) δ; 9.52, 11.04, 14.93, 16.53, 16.62, 18.97, 21.50, 21.77, 21.88, 27.17, 27.51, 29.02, 33.59, 35.43, 37.95, 39.32, 40.65, 65.79, 65.86, 69.19. 70.58, 71.33, 73.04, 74.66, 75.31, 77.23, 80.44, 83.70, 95.86, 96.67, 103.42, 115.00, 115.05, 118.82, 150.80, 155.47, 174.31, 175.57. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 9.52, 11.04, 14.93, 16.53, 16.62, 18.97, 21.50, 21.77, 21.88, 27.17, 27.51, 29.02, 33.59, 35.43, 37.95, 39.32, 40.65, 65.79, 65.86, 69.19. 70.58, 71.33, 73.04, 74.66, 75.31, 77.23, 80.44, 83.70, 95.86, 96.67, 103.42, 115.00, 115.05, 118.82, 150.80, 155.47, 174.31, 175.57.

IR(KBr, cm-1) 3455, 2976, 2877, 2787, 1745, 1651, 1516, 1466, 1391, 1352, 1212, 1182, 1062, 1028, 898, 853.IR (KBr, cm −1 ) 3455, 2976, 2877, 2787, 1745, 1651, 1516, 1466, 1391, 1352, 1212, 1182, 1062, 1028, 898, 853.

실시예 3Example 3

6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](5)의제조.6- (4-Dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-trimethylsilyl -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Preparation of 10- [O- (4-methoxy-phenoxymethyl) -oxime] (5).

화합물 (1)(2.26 g,2.56 mmol)을 DMF에 녹이고 NH4Cl(205 mg,3.84 mmol)을 한번에 넣고, 헥사메틸다이실라잔(1.19 ml,5.63 mmol)을 적가하였다. 이 혼합 용액을 50℃에서 3시간 동안 교반시켰다. 반응 혼합물을 헥산(45 ml)과 증류수(45 ml)에 부어 교반한 후, 헥산(50 ml x 3)으로 추출하고, 유기층을 포화 소금물과 5% NaHCO3수용액으로 순차 세척하고, MgSO4로 건조시켰다. 건조제를 사용한 여과를 수행하고, 여액을 감압 농축시키고 진공 건조시켜 거품형 고체를 정량적으로 얻었다.Compound (1) (2.26 g, 2.56 mmol) was dissolved in DMF and NH 4 Cl (205 mg, 3.8 mmol) was added in one portion, and hexamethyldisilazane (1.19 ml, 5.63 mmol) was added dropwise. This mixed solution was stirred at 50 ° C. for 3 hours. The reaction mixture was poured into hexane (45 ml) and distilled water (45 ml), stirred, extracted with hexane (50 ml x 3), and the organic layer was washed sequentially with saturated brine and 5% aqueous NaHCO 3 solution and dried over MgSO 4 . I was. Filtration with a drying agent was carried out, and the filtrate was concentrated under reduced pressure and dried in vacuo to quantitatively obtain a foamy solid.

TLC: Rf=0.88(CH2Cl2/MeOH/c-NH4OH=100/5/1)TLC: R f = 0.88 (CH 2 Cl 2 / MeOH / c-NH 4 OH = 100/5/1)

FAB-MS : M+= 1029FAB-MS: M + = 1029

1H-NMR(CDCl3, 300 MHz) δ 0.00(s, 9H), 0.06(s, 9H), 0.76(m, 5H), 0.87(d, J=6.84 Hz, 3H), 0.96(d, J=7.32 Hz, 3H), 1.06(m, 18H), 1.25(bs, 3H), 1.42(m, 7H), 1.84(m, 2H), 2,12(s,6H), 1.35(m, 1H), 1.48(m, 1H), 1.72(m, 1H), 3.03(m, 3H), 3.21(s, 3H), 3.32(m, 3H), 3.68(s, 3H), 4.03(m,2H), 4.27(d, J=7.05 Hz,1H), 4.76(d, J=4.58 Hz,1H), 5.01(dd, J=10.73 Hz, 2.28 Hz 1Hz), 5.50(dd, J=25.26 Hz, 7.28 Hz), 6.74(m, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.00 (s, 9H), 0.06 (s, 9H), 0.76 (m, 5H), 0.87 (d, J = 6.84 Hz, 3H), 0.96 (d, J = 7.32 Hz, 3H), 1.06 (m, 18H), 1.25 (bs, 3H), 1.42 (m, 7H), 1.84 (m, 2H), 2,12 (s, 6H), 1.35 (m, 1H) , 1.48 (m, 1H), 1.72 (m, 1H), 3.03 (m, 3H), 3.21 (s, 3H), 3.32 (m, 3H), 3.68 (s, 3H), 4.03 (m, 2H), 4.27 (d, J = 7.05 Hz, 1H), 4.76 (d, J = 4.58 Hz, 1H), 5.01 (dd, J = 10.73 Hz, 2.28 Hz 1Hz), 5.50 (dd, J = 25.26 Hz, 7.28 Hz) , 6.74 (m, 4H)

13C-nmr(CDCl3, 75.5 MHz) δ; 0.00(OSi(CH3)3), 8.73, 9.87, 13.51, 15.23, 17.63, 18.39, 20.86, 21.26, 25.97, 26.24, 28.76, 30.68, 32.46, 34.98, 37.35, 39.04, 40.06, 43.81, 48.81, 54.67, 64.03, 64.19, 66.77, 69.33, 72.26, 72.36, 73.44, 74.32, 75.99, 78.65, 80.05, 80.65, 94.71, 95.68(C-1', 101.79(C-1', 113.73, 117.53, 149.74, 154.14, 172.65, 174.88(C=N). 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 0.00 (OSi (CH 3 ) 3 ), 8.73, 9.87, 13.51, 15.23, 17.63, 18.39, 20.86, 21.26, 25.97, 26.24, 28.76, 30.68, 32.46, 34.98, 37.35, 39.04, 40.06, 43.81, 48.81, 54.67, 64.03, 64.19, 66.77, 69.33, 72.26, 72.36, 73.44, 74.32, 75.99, 78.65, 80.05, 80.65, 94.71, 95.68 (C-1 ', 101.79 (C-1', 113.73, 117.53, 149.74, 154.14, 172.65, 174.88 (C = N).

IR(KBr, cm-1) 3525, 2986, 2777, 1755, 1521, 1471, 1381, 1347, 1257, 1227, 1182, 1102, 1026, 908.IR (KBr, cm −1 ) 3525, 2986, 2777, 1755, 1521, 1471, 1381, 1347, 1257, 1227, 1182, 1102, 1026, 908.

실시예 4Example 4

6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](6)의 제조6- (4-Dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-trimethel Silyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-da Preparation of Ion 10- [O- (2-methoxy-phenoxymethyl) -oxime] (6)

실시예 3과 같은 방법으로 반응시켜 정량적으로 화합을(6)을 얻었다.The reaction was carried out in the same manner as in Example 3 to obtain quantitatively compound (6).

TLC: Rf=0.7(CH2Cl2/MeOH/c-NH4OH=100/5/2)TLC: R f = 0.7 (CH 2 Cl 2 / MeOH / c-NH 4 OH = 100/5/2)

FAB-MS : M+= 1029FAB-MS: M + = 1029

1H-NMR(CDCl3, 300 MHz) δ 0.01(s, 9H, 2'-OSi(CH3)3), 0.15(s, 9H, 4'-OSi(CH3)3), 0.81~1.68(m, 48H), 1.84(m, 1H), 2.26(s, 6H, N(CH3)2), 2.34(m, 1H), 3.34(s,3H, 3'-OCH3), 3.43(s, 3H, OCH3), 4.44(d, J=7.2 Hz, 1H), 4.90(d, J=4.58 Hz, 1H), 5.14(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.64(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 7.00(m, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.01 (s, 9H, 2'-OSi (CH 3 ) 3 ), 0.15 (s, 9H, 4'-OSi (CH 3 ) 3 ), 0.81 to 1.68 ( m, 48H), 1.84 (m, 1H), 2.26 (s, 6H, N (CH 3 ) 2 ), 2.34 (m, 1H), 3.34 (s, 3H, 3′-OCH 3 ), 3.43 (s, 3H, OCH 3 ), 4.44 (d, J = 7.2 Hz, 1H), 4.90 (d, J = 4.58 Hz, 1H), 5.14 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.64 (dd, J = 30,21 Hz, 7.08 Hz, NO-CH 2 -O-), 7.00 (m, 4H)

IR(KBr, cm-1) 3505, 2996, 2937, 1750, 1606, 1506, 1466, 1386, 1352, 1262, 1177, 1132, 1062, 1023, 908, 848.IR (KBr, cm −1 ) 3505, 2996, 2937, 1750, 1606, 1506, 1466, 1386, 1352, 1262, 1177, 1132, 1062, 1023, 908, 848.

실시예 5Example 5

6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](7)의 제조6- (4-Dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4- (5 -Trimethylsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 Preparation of -dione 10- [O- (4-methoxy-phenoxymethyl) -oxime] (7)

화합물 (5)(1 g,0.97 mmol)을 DMSO(5 ml)/THF(5 ml)에 녹이고 얼음조를 이용하여 -5℃~0℃로 낮춘 후 가루상태의 KOH(128 mg,1.94 mmol)와 CH3I(0.15 ml, 2.42 mmol)을 한번에 가하고 온도를 0℃이하로 유지시키고 2시간 30분 동안 반응시켰다. CH3I 0.54 ml를 넣고, 반응 혼합물을 헥산(50 ml)/증류수(50 ml)에 부어 5분간 교반한 후, 유기층을 분리하고 수용층을 헥산(20 ml x 2)으로 추출한 후 유기층을 합하여 MgSO4로 건조시키고, 감압 농축시켜 흰색 거품상 고체를 얻었다.Compound (5) (1 g, 0.97 mmol) was dissolved in DMSO (5 ml) / THF (5 ml) and lowered to -5 ° C to 0 ° C using an ice bath, and then powdered KOH (128 mg, 1.94 mmol). And CH 3 I (0.15 ml, 2.42 mmol) were added at once, and the temperature was kept below 0 ° C. and reacted for 2 hours and 30 minutes. 0.54 ml of CH 3 I was added, the reaction mixture was poured into hexane (50 ml) / distilled water (50 ml), stirred for 5 minutes, the organic layer was separated, the aqueous layer was extracted with hexane (20 ml x 2), and the organic layers were combined and MgSO. 4 dried and concentrated under reduced pressure to give a white foamy solid.

수율 : 742 mg(73%)Yield: 742 mg (73%)

FAB-MS : M+= 1043FAB-MS: M + = 1043

1H-NMR(CDCl3, 300MHz) δ -0.07(s, 9H, 2'-OSi(CH3)3), -0.01(s, 4'-OSi(CH3)3, 9H), 0.71(m, 7H), 0.89(d, J=7.41 Hz, 3H), 1.05(m, 24H), 1.23(s, 3H), 2.06(s, 6H, N(CH3)2), 2.41(m, 1H), 2.65(m, 1H), 2.79(3, 3H, 7-OCH3), 2.99(m, 3H), 3.15(s, 3H, 3'-OCH3), 3.44(m, 3H), 3.61(s, 3H, ph-OCH3), 4.06(m,1H), 4.23(d, J=7.02 Hz, 1H, 1'-H), 4.73(d, J=4.74 Hz),4.96(dd, J=10.8 Hz, 1.57 Hz, 1H), 5.43(dd ,J=23.09 Hz, 7.53 Hz,1H), 6.69(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ -0.07 (s, 9H, 2'-OSi (CH 3 ) 3 ), -0.01 (s, 4'-OSi (CH 3 ) 3 , 9H), 0.71 (m , 7H), 0.89 (d, J = 7.41 Hz, 3H), 1.05 (m, 24H), 1.23 (s, 3H), 2.06 (s, 6H, N (CH 3 ) 2 ), 2.41 (m, 1H) , 2.65 (m, 1H), 2.79 (3, 3H, 7-OCH 3 ), 2.99 (m, 3H), 3.15 (s, 3H, 3'-OCH 3 ), 3.44 (m, 3H), 3.61 (s , 3H, ph-OCH 3 ), 4.06 (m, 1H), 4.23 (d, J = 7.02 Hz, 1H, 1′-H), 4.73 (d, J = 4.74 Hz), 4.96 (dd, J = 10.8 Hz, 1.57 Hz, 1H), 5.43 (dd, J = 23.09 Hz, 7.53 Hz, 1H), 6.69 (m, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 0.00, 0.16, 8.73, 9.78, 14.13, 15.22, 17.66, 18.45, 19.36, 20.32, 21.06, 21.30, 21.76, 26.13, 28.65, 30.70, 32.39, 34.89, 36.90, 38.64, 40.09, 44.41, 48.83, 49.86(C-7-OCH3), 54.75, 64.21, 66.36, 68.92, 72.25, 72.40, 73.13, 75.82, 77.12, 78.00, 78.10, 79.9594.66, 95.32, 101.71, 113.57, 116.95, 150.40, 153.85, 171.71, 175.06. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 0.00, 0.16, 8.73, 9.78, 14.13, 15.22, 17.66, 18.45, 19.36, 20.32, 21.06, 21.30, 21.76, 26.13, 28.65, 30.70, 32.39, 34.89, 36.90, 38.64, 40.09, 44.41, 48.83, 49.86 (C- 7-OCH 3 ), 54.75, 64.21, 66.36, 68.92, 72.25, 72.40, 73.13, 75.82, 77.12, 78.00, 78.10, 79.9594.66, 95.32, 101.71, 113.57, 116.95, 150.40, 153.85, 171.71, 175.06.

IR(KBr, cm-1)3535, 3455, 2976, 2827, 1740, 1516, 1471, 1386, 1367, 1252, 1212, 1177, 1122, 1107, 1043, 1023, 908.IR (KBr, cm −1 ) 3535, 3455, 2976, 2827, 1740, 1516, 1471, 1386, 1367, 1252, 1212, 1177, 1122, 1107, 1043, 1023, 908.

실시예 6Example 6

6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](8)의 제조6- (4-Dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-trihydroxy-4- (5 -Trimethelsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotedecane-2, Preparation of 10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime] (8)

실시예 5와 같은 방법으로 화합물 (6)으로 부터 제조하였다.Prepared from compound (6) in the same manner as in Example 5.

수율: 74%Yield: 74%

FAB-MS : M+= 1043FAB-MS: M + = 1043

1H-NMR(CDCl3, 300 MHz) δ 0.07(s, 9H, 2'-OSi(CH3)3), 0.15(s, 4'-OSi(CH3)3, 9H), 0.78(m, 7H), 1.15(m, 27H), 1.38(s, 3H), 2.21(s, 6H, N(CH3)2), 2.41(m, 1H), 2.65(m, 1H), 2.97(s, 3H, 7-OCH3), 3.12(m, 3H), 3.30(s, 3H, 3'-OCH3), 3.64(m, 3H), 3.85(s, 3H, ph-OCH3), 4.16(m, 1H), 4.44(d, J=7.2 Hz, 1H), 4.90(d, J=4.58 Hz, 1H), 5.14(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.64(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 7.00(m, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.07 (s, 9H, 2′-OSi (CH 3 ) 3 ), 0.15 (s, 4'-OSi (CH 3 ) 3 , 9H), 0.78 (m, 7H), 1.15 (m, 27H), 1.38 (s, 3H), 2.21 (s, 6H, N (CH 3 ) 2 ), 2.41 (m, 1H), 2.65 (m, 1H), 2.97 (s, 3H , 7-OCH 3 ), 3.12 (m, 3H), 3.30 (s, 3H, 3'-OCH 3 ), 3.64 (m, 3H), 3.85 (s, 3H, ph-OCH 3 ), 4.16 (m, 1H), 4.44 (d, J = 7.2 Hz, 1H), 4.90 (d, J = 4.58 Hz, 1H), 5.14 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.64 (dd, J = 30, 21 Hz, 7.08 Hz, NO-CH 2 -O-), 7.00 (m, 4H)

IR(KBr, cm-1) 3525, 2986, 1755, 1506, 1471, 1386, 1352, 1252, 1182, 1107, 1067, 1013, 918, 858IR (KBr, cm -1 ) 3525, 2986, 1755, 1506, 1471, 1386, 1352, 1252, 1182, 1107, 1067, 1013, 918, 858

실시예 7Example 7

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](2)의 제조.6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4- (5 -Hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 Preparation of -dione 10- [O- (4-methoxy-phenoxymethyl) -oxime] (2).

실시예 5에서 제조된 화합물 (7)(1.5 g, 1.43 mmol)을 메탄올 20 ml에 녹이고 개미산(0.244 ml, 6.46 mmol)을 한번에 가하고, 40℃에서 3시간 동안 반응시킨 후, 1M NaOH로 pH를 9로 맞춘 후 증류수 100 ml에 부어 고체를 생성시켰다. 생성된 고체를 여과하여 증류수로 철저히 씻어낸 후 상온에서 건조시키고, 진공건조시켜 1.17g의 흰색고체를 얻었다.Compound (7) (1.5 g, 1.43 mmol) prepared in Example 5 was dissolved in 20 ml of methanol, formic acid (0.244 ml, 6.46 mmol) was added at once, and reacted at 40 ° C. for 3 hours, and then the pH was adjusted with 1 M NaOH. 9 and then poured into 100 ml of distilled water to form a solid. The resulting solid was filtered, washed thoroughly with distilled water, dried at room temperature and dried in vacuo to yield 1.17 g of a white solid.

수율:91%Yield: 91%

FAB-MS : M+= 972FAB-MS: M + = 972

1H-NMR(CDCl3, 300 MHz) δ 0.74(m, 6H), 1.19(m, 40H), 1.74(m, 2H), 2.12(s, 6H, N(CH3)2), 2.41(m, 1H), 2.78(s, 3H, 7-OCH3), 3.30(m, 2H), 3.47(m, 3H), 3.60(s, 3H, ph-OCH3), 3.84(m, 1H), 4.18(m, 1H), 4.25(m, 1H), 4.76(bs, 1H), 4.93(d, J=10.4 Hz, 1H), 5.37(m, 2H), 6.64(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.74 (m, 6H), 1.19 (m, 40H), 1.74 (m, 2H), 2.12 (s, 6H, N (CH 3 ) 2 ), 2.41 (m , 1H), 2.78 (s, 3H, 7-OCH 3 ), 3.30 (m, 2H), 3.47 (m, 3H), 3.60 (s, 3H, ph-OCH 3 ), 3.84 (m, 1H), 4.18 (m, 1H), 4.25 (m, 1H), 4.76 (bs, 1H), 4.93 (d, J = 10.4 Hz, 1H), 5.37 (m, 2H), 6.64 (m, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 8.20, 9.76, 14.17, 14.60, 17.72, 19.19, 19.66, 21.00, 21.30, 26.23, 27.72, 32.34, 33.99, 36.51, 38.10, 39.39, 44.16, 48.60, 49.97(7- OCH3), 54.75, 64.62, 64.73, 66.90, 67.76, 68.92, 70.11, 71.78, 73.10, 75.93, 77.07, 77.41, 77.71, 79.41, 95.13, 101.84,113.72, 116.94, 150.36, 153.86, 171.75, 174.80. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 8.20, 9.76, 14.17, 14.60, 17.72, 19.19, 19.66, 21.00, 21.30, 26.23, 27.72, 32.34, 33.99, 36.51, 38.10, 39.39, 44.16, 48.60, 49.97 (7-OCH 3 ), 54.75, 64.62, 64.73, 66.90, 67.76, 68.92, 70.11, 71.78, 73.10, 75.93, 77.07, 77.41, 77.71, 79.41, 95.13, 101.84,113.72, 116.94, 150.36, 153.86, 171.75, 174.80.

IR(KBr, cm-1) 3505, 2992, 2957, 1740, 1516, 1476, 1381, 1352, 1217, 1177, 1122, 1087, 1057, 1033.903, 838.IR (KBr, cm −1 ) 3505, 2992, 2957, 1740, 1516, 1476, 1381, 1352, 1217, 1177, 1122, 1087, 1057, 1033.903, 838.

실시예 8Example 8

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](4)의 제조.6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4- (5 -Hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 Preparation of -dione 10- [O- (2-methoxy-phenoxymethyl) -oxime] (4).

실시예 7과 같은 방법으로 제조하였다.It prepared in the same manner as in Example 7.

수율:91%Yield: 91%

1H-NMR(CDCl3, 300 MHz) δ; 1.03(m, 6H), 1.06~1.72(m, 40H), 2.32(s, 6H, N(CH3)2), 2.58(m, 1H), 2.96(s, 3H, 7-OCH3), 2.96(m, 2H), 3.31(s, 3H, 3'-OCH3), 3.60(m, 6H), 3.84(s, 3H, ph-OCH3), 4.25(s, 1H), 4.40(d, J=7.11 Hz, 1H, 1'-H), 4.90(d, J=4.59 Hz, 1H, 1'-H), 5.14(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.64(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ; 1.03 (m, 6H), 1.06 to 1.72 (m, 40H), 2.32 (s, 6H, N (CH 3 ) 2 ), 2.58 (m, 1H), 2.96 (s, 3H, 7-OCH 3 ), 2.96 (m, 2H), 3.31 (s, 3H, 3'-OCH 3 ), 3.60 (m, 6H), 3.84 (s, 3H, ph-OCH 3 ), 4.25 (s, 1H), 4.40 (d, J = 7.11 Hz, 1H, 1'-H, 4.90 (d, J = 4.59 Hz, 1H, 1'-H), 5.14 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.64 (dd, J = 30, 21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H).

IR(KBr, cm-1) 3475, 2976, 2927, 1740, 1506, 1471, 1381, 1267, 1187, 1122, 1092, 1062, 1023, 903, 768.IR (KBr, cm −1 ) 3475, 2976, 2927, 1740, 1506, 1471, 1381, 1267, 1187, 1122, 1092, 1062, 1023, 903, 768.

실시예 9Example 9

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](9)의 제조.6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy-3, Preparation of 5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime] (9).

실시예 8에서 제조된 화합물 (9)(4.07 g, 3.9 mmol)를 메탄올(50 ml)/증류수(150 ml)에 녹이고 12N 염산(3.22 ml, 39 mmol)을 적가하고 상온에서 5시간 동안 교반하였다. 이 반응 혼합물을 NaCl(33.5 g)와 NH4Cl(3 ml)로 pH를 8로맞춘 후 CH2Cl2로 추출하고, 유기층을 MgSO4로 건조시킨 후 농축하여 흰색 고체를 얻었다. 이 고체를 실리카겔 컬럼크로마토그래피로 해당부분을 분리한 후 농축하여 2.34 g의 목적 화합물을 얻었다.Compound (9) (4.07 g, 3.9 mmol) prepared in Example 8 was dissolved in methanol (50 ml) / distilled water (150 ml) and 12N hydrochloric acid (3.22 ml, 39 mmol) was added dropwise and stirred at room temperature for 5 hours. . The reaction mixture was adjusted to pH 8 with NaCl (33.5 g) and NH 4 Cl (3 ml), extracted with CH 2 Cl 2 , the organic layer was dried over MgSO 4 and concentrated to give a white solid. This solid was separated by silica gel column chromatography and concentrated to give 2.34 g of the title compound.

수율: 81%Yield: 81%

FAB-MS : M+= 742FAB-MS: M + = 742

1H-NMR(CDCl3, 300 MHz) δ; 0.83(t, J=7.32 Hz, 3H), 0.92(d, J=7.00 Hz, 3H), 1.05(d, J=7.33 Hz, 3H), 1.08~1.69(m, 22H), 1.91~2.08(m, 2H), 2.24(s, 6H, N(CH3)2), 2.45(m,1H), 2.68(s, 3H, 7-OCH3), 3.19(dd, J=10.26 Hz, 7.34 Hz, 1H), 3.29(s, 1H), 3.49(m, 5H), 3.76(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.34(m, 2H), 5.20(dd, J=11.07 Hz, 2.35 Hz, 1H), 5.30(s, 1H), 5.54(dd, J=10.25 Hz, 7.7 Hz, 2H), 6.79(dd, J=43.27 Hz, 9.08 Hz, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ; 0.83 (t, J = 7.32 Hz, 3H), 0.92 (d, J = 7.00 Hz, 3H), 1.05 (d, J = 7.33 Hz, 3H), 1.08 to 1.69 (m, 22H), 1.91 to 2.08 (m , 2H), 2.24 (s, 6H, N (CH 3 ) 2 ), 2.45 (m, 1H), 2.68 (s, 3H, 7-OCH 3 ), 3.19 (dd, J = 10.26 Hz, 7.34 Hz, 1H ), 3.29 (s, 1H), 3.49 (m, 5H), 3.76 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.34 (m, 2H), 5.20 (dd, J = 11.07 Hz , 2.35 Hz, 1H), 5.30 (s, 1H), 5.54 (dd, J = 10.25 Hz, 7.7 Hz, 2H), 6.79 (dd, J = 43.27 Hz, 9.08 Hz, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 8.88, 11.17, 15.82, 16.07, 16.91, 18.93, 19.45, 21.95, 22.28, 27.65, 28.62, 34.07, 36.50, 37.98, 40.93, 45.26, 50.04, 56.35, 66.30, 70.96, 71.06, 71.33, 74.68, 77.52, 78.93, 79.55, 89.02, 95.92, 107.60, 115.08, 118.09, 152.04, 155.25, 172.73, 175.59. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 8.88, 11.17, 15.82, 16.07, 16.91, 18.93, 19.45, 21.95, 22.28, 27.65, 28.62, 34.07, 36.50, 37.98, 40.93, 45.26, 50.04, 56.35, 66.30, 70.96, 71.06, 71.33, 74.68, 77.52, 78.93 79.55, 89.02, 95.92, 107.60, 115.08, 118.09, 152.04, 155.25, 172.73, 175.59.

실시예 10Example 10

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심] (10)의 제조.6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy-3, Preparation of 5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime] (10).

실시예 9와 같은 방법으로 제조하였다.It prepared in the same manner as in Example 9.

수율: 82%Yield: 82%

1H-NMR(CDCl3, 300 MHz) δ; 0.83(t, J=7.32 Hz, 3H), 0.90(d, J=7.00 Hz, 3H), 1.05~1.69(m, 22H), 1.91~2.08(m, 2H), 2.24(s, 6H, N(CH3)2), 2.57(m, 5H), 2.66(s, 3H, 7-OCH3), 2.98(s, 1H), 3.30(m, 3H), 3.48(m, 9H), 3.85(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.29(s, 1H), 4.34(d, J=7.11 Hz, 1H, 1'-H), 5.20(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.68(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ; 0.83 (t, J = 7.32 Hz, 3H), 0.90 (d, J = 7.00 Hz, 3H), 1.05-1.69 (m, 22H), 1.91-2.08 (m, 2H), 2.24 (s, 6H, N ( CH 3 ) 2 ), 2.57 (m, 5H), 2.66 (s, 3H, 7-OCH 3 ), 2.98 (s, 1H), 3.30 (m, 3H), 3.48 (m, 9H), 3.85 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.29 (s, 1H), 4.34 (d, J = 7.11 Hz, 1H, 1'-H), 5.20 (dd, J = 10.73 Hz, 2.28 Hz , 1H), 5.68 (dd, J = 30, 21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 8.61, 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 44.495, 49.77, 56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79.20, 88.29, 95.97, 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 175.37. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 8.61, 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 44.495, 49.77, 56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79.20, 88.29, 88.29 95.97, 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 175.37.

실시예 11Example 11

아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(4-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르(11)의 제조.Acetic acid 4-dimethylamino-2- [14-ethyl-4,12,12-trihydroxy-7-methoxy-10 (4-methoxyphenoxymethoxyimino) -3,5,7,9, Preparation of 11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl-ester (11).

실시예 9에서 제조된 화합물 (9)(2 g, 2.69 mmol)을 아세톤 30 ml에 녹이고 K2CO3(743 mg,5.38 mmol)와 아세트산 무수물(0.264 ml, 2.97 mmol)을 한번에 넣고 16시간 동안 반응시켰다. 이 반응 혼합물에 얼음을 넣은 후, CH2Cl2(50 ml x 3)으로 추출하였다. 유기층을 포화 NaHCO3수용액(20 ml)과 증류수(30 ml)로 순차 세척하고, MgSO4로 건조시킨 후 여과하였다. 여과액을 감압 농축하여 흰색 고체 2.08 g을 얻었다.Compound (9) (2 g, 2.69 mmol) prepared in Example 9 was dissolved in 30 ml of acetone, and K 2 CO 3 (743 mg, 5.38 mmol) and acetic anhydride (0.264 ml, 2.97 mmol) were added at a time for 16 hours. Reacted. Ice was added to the reaction mixture, which was then extracted with CH 2 Cl 2 (50 ml × 3). The organic layer was washed sequentially with saturated NaHCO 3 aqueous solution (20 ml) and distilled water (30 ml), dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 2.08 g of a white solid.

수율 : 99%Yield: 99%

FAB-MS : M+= 783FAB-MS: M + = 783

1H-NMR(CDCl3, 300 MHz) δ 0.83(t, J=7.35 Hz, 3H), 0.92(d, J=6.87 Hz, 3H), 1.05(d, J=7.32 Hz, 3H), 1.14(m, 22H), 1.91(m, 2H), 2.05(s, 3H, 2'Ac), 2.24(s, 6H, N(CH3)2), 2.43(m, 1H), 2.57(m, 2H), 2.68(s, 3H, 7-OCH3), 3.19(dd, J=10.24 Hz, 7.31 Hz, 1H), 3.47(m, 4H), 3.76(s, 3H, ph-OCH3), 4.32(m, 1H), 5.20(dd, J=2.24 Hz, 11.07 Hz,1H), 5.54(dd, J=7.65 Hz, 2.90 Hz, 2H), 6.79(dd, J=40.92Hz, 9.09 Hz, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.83 (t, J = 7.35 Hz, 3H), 0.92 (d, J = 6.87 Hz, 3H), 1.05 (d, J = 7.32 Hz, 3H), 1.14 ( m, 22H), 1.91 (m, 2H), 2.05 (s, 3H, 2'Ac), 2.24 (s, 6H, N (CH 3 ) 2 ), 2.43 (m, 1H), 2.57 (m, 2H) , 2.68 (s, 3H, 7-OCH 3 ), 3.19 (dd, J = 10.24 Hz, 7.31 Hz, 1H), 3.47 (m, 4H), 3.76 (s, 3H, ph-OCH 3 ), 4.32 (m , 1H), 5.20 (dd, J = 2.24 Hz, 11.07 Hz, 1H), 5.54 (dd, J = 7.65 Hz, 2.90 Hz, 2H), 6.79 (dd, J = 40.92 Hz, 9.09 Hz, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 8.85, 11.14, 15.79, 16.03, 16.88, 18.91,19.43, 21.92, 22.26, 27.63, 28.66, 34.05, 36.48, 37.97, 40.89, 41.31, 45.23, 50.02, 56.32, 66.28, 70.89, 71.04, 71.31, 74.66, 77.49, 78.82, 79.50, 88.90, 100.41, 107.50, 115.06, 118.19, 152.01,155.24, 172.71, 175.56. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 8.85, 11.14, 15.79, 16.03, 16.88, 18.91,19.43, 21.92, 22.26, 27.63, 28.66, 34.05, 36.48, 37.97, 40.89, 41.31, 45.23, 50.02, 56.32, 66.28, 70.89, 71.04, 71.31, 74.66, 77.49, 77.49 78.82, 79.50, 88.90, 100.41, 107.50, 115.06, 118.19, 152.01,155.24, 172.71, 175.56.

실시예 12Example 12

아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(2-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르(12)의 제조.Acetic acid 4-dimethylamino-2- [14-ethyl-4,12,12-trihydroxy-7-methoxy-10 (2-methoxyphenoxymethoxyimino) -3,5,7,9, Preparation of 11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl-ester (12).

실시예 11과 같은 방법으로 제조하였다.It prepared in the same manner as in Example 11.

수율: 97%Yield: 97%

1H-NMR(CDCl3, 300 MHz) δ 0.83(t, J=7.32 Hz, 3H), 0.90(d, J=7.00 Hz, 3H), 1.05~1.69(m, 22H), 1.91(m, 2H), 2.05(s, 3H), 2.24(s, 6H, N(CH3)2), 2.57(m, 5H), 2.66(s, 3H, 7-OCH3), 2.98(s, 1H), 3.30(m, 3H), 3.48(m, 9H), 3.85(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.29(s, 1H), 4.34(d, J=7.11 Hz, 1H, 1'-H), 5.20(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.68(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.83 (t, J = 7.32 Hz, 3H), 0.90 (d, J = 7.00 Hz, 3H), 1.05-1.69 (m, 22H), 1.91 (m, 2H ), 2.05 (s, 3H), 2.24 (s, 6H, N (CH 3 ) 2 ), 2.57 (m, 5H), 2.66 (s, 3H, 7-OCH 3 ), 2.98 (s, 1H), 3.30 (m, 3H), 3.48 (m, 9H), 3.85 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.29 (s, 1H), 4.34 (d, J = 7.11 Hz, 1H, 1'-H), 5.20 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.68 (dd, J = 30,21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H) .

13C-nmr(CDCl3, 75.5 MHz) δ; 8.61, 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 41.34, 44.95, 49.77,56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79.20, 88.29, 100.39, 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 175.37 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 8.61, 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 41.34, 44.95, 49.77,56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79. 88.29, 100.39, 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 175.37

실시예 13Example 13

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(4-메톡시-페녹시메틸)-옥심](13) 의 제조.6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy-3, Preparation of 5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (4-methoxy-phenoxymethyl) -oxime] (13).

화합물 (11)(2.05 g, 2.61 mmol)을 아세톤 50 ml에 녹이고, 증류수(1 ml)에 CrO3(523 mg, 5.23 mmol)을 녹인 후 황산(0.322 ml, 5.8 mmol)을 넣은 용액을 아세톤 혼합물에 적가하고 0℃에서 2시간 반응시켰다. 이 반응 혼합물에 1-프로판올 1 ml를 넣고 감압 농축시킨 후, 잔사를 증류수(10 ml) 및 CH2Cl2(25 ml)에 녹이고 K2CO3로 pH를 8로 맞춘 후 CH2Cl2(50 ml x 3)으로 추출한 후 유기층을 포화 소금물(20 ml)과 증류수(30 ml)로 순차 세척한 후 MgSO4로 건조하고 여과하였다. 여과액을 감압 농축시킨 후, 점성용액을 메탄올 20 ml에 녹여 24시간 동안 교반시킨 후 실리카겔 컬럼크로마토그래피로 정제 시켜 해당부분을 농축하여 1.03 g의 목적화합물을 얻었다.Compound (11) (2.05 g, 2.61 mmol) was dissolved in 50 ml of acetone, CrO 3 (523 mg, 5.23 mmol) was dissolved in distilled water (1 ml), and a solution of sulfuric acid (0.322 ml, 5.8 mmol) was added to the acetone mixture. It was added dropwise thereto and reacted at 0 ° C. for 2 hours. 1 ml of 1-propanol was added to the reaction mixture and concentrated under reduced pressure. The residue was dissolved in distilled water (10 ml) and CH 2 Cl 2 (25 ml), and the pH was adjusted to 8 with K 2 CO 3 , followed by CH 2 Cl 2 ( After extraction with 50 ml x 3), the organic layer was washed sequentially with saturated brine (20 ml) and distilled water (30 ml), dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure, the viscous solution was dissolved in 20 ml of methanol, stirred for 24 hours, purified by silica gel column chromatography, and concentrated to obtain 1.03 g of the target compound.

수율 : 55 %Yield: 55%

FAB-MS : M+= 739FAB-MS: M + = 739

1H-NMR(CDCl3, 300 MHz) δ 0.82(t, J=7.07 Hz, 3H), 0.92(d, J=6.71 Hz,3H), 1.13(d, J=6.68 Hz, 3H), 1.22(m, 25H), 2.01(m, 1H), 2.26(s, 6H, N(CH3)2), 2.52(s, 3H, 7-OCH3), 2.57(d, J=9.89 Hz, 2H), 3.15(m, 2H), 3.53(m, 3H), 3.75(s, 3H, ph-OCH3), 3.81(m, 2H), 4.26(m, 3H), 5.15(d, J=9.91 Hz, 1H), 5.52(dd, J=20.52 Hz, 7.58 Hz, 2H), 6.77(dd, J=37.87 Hz, 8.81 Hz, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.82 (t, J = 7.07 Hz, 3H), 0.92 (d, J = 6.71 Hz, 3H), 1.13 (d, J = 6.68 Hz, 3H), 1.22 ( m, 25H), 2.01 (m, 1H), 2.26 (s, 6H, N (CH 3 ) 2 ), 2.52 (s, 3H, 7-OCH 3 ), 2.57 (d, J = 9.89 Hz, 2H), 3.15 (m, 2H), 3.53 (m, 3H), 3.75 (s, 3H, ph-OCH 3 ), 3.81 (m, 2H), 4.26 (m, 3H), 5.15 (d, J = 9.91 Hz, 1H ), 5.52 (dd, J = 20.52 Hz, 7.58 Hz, 2H), 6.77 (dd, J = 37.87 Hz, 8.81 Hz, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 11.19, 14.82, 15.00, 15.52, 16.73, 18.95, 20.18, 21.76, 22.01, 27.57, 28.77, 33.78, 38.47, 40.77, 47.00, 50.16, 51.42, 56.17, 66.35, 69.96, 70.45, 70.83, 74.26, 78.19, 78.56, 95.71, 103.95, 114.96, 118.02, 151.65, 155.22, 169.90, 172.55, 205.96. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 11.19, 14.82, 15.00, 15.52, 16.73, 18.95, 20.18, 21.76, 22.01, 27.57, 28.77, 33.78, 38.47, 40.77, 47.00, 50.16, 51.42, 56.17, 66.35, 69.96, 70.45, 70.83, 74.26, 78.19, 78.56, 78.56, 78.56, 78.56 95.71, 103.95, 114.96, 118.02, 151.65, 155.22, 169.90, 172.55, 205.96.

IR(KBr, cm-1) 3495, 2996, 2947, 2907, 2847, 1750, 1521, 1476, 1386, 1352, 1232, 1192, 1122, 1882, 1048, 998.IR (KBr, cm −1 ) 3495, 2996, 2947, 2907, 2847, 1750, 1521, 1476, 1386, 1352, 1232, 1192, 1122, 1882, 1048, 998.

실시예 14Example 14

6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(2-메톡시-페녹시메틸)-옥심](14)의 제조.6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy-3, Preparation of 5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (2-methoxy-phenoxymethyl) -oxime] (14).

실시예 13과 같은 방법으로 제조하였다.It prepared in the same manner as in Example 13.

수율 : 51%Yield: 51%

1H-NMR(CDCl3, 300 MHz) δ 0.83(t, J=7.32 Hz, 3H), 0.90(d, J=7.00 Hz,3H), 1.05~1.69(m, 22H), 1.91(m, 2H), 2.24(s, 6H, N(CH3)2), 2.57(m, 5H), 2.66(s, 3H, 7-OCH3), 2.98(s, 1H), 3.30(m, 3H), 3.48(m, 9H), 3.85(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.29(s, 1H), 4.34(d, J=7.11 Hz, 1H,), 5.20(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.68(dd, J=30.21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.83 (t, J = 7.32 Hz, 3H), 0.90 (d, J = 7.00 Hz, 3H), 1.05-1.69 (m, 22H), 1.91 (m, 2H ), 2.24 (s, 6H, N (CH 3 ) 2 ), 2.57 (m, 5H), 2.66 (s, 3H, 7-OCH 3 ), 2.98 (s, 1H), 3.30 (m, 3H), 3.48 (m, 9H), 3.85 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.29 (s, 1H), 4.34 (d, J = 7.11 Hz, 1H,), 5.20 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.68 (dd, J = 30.21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H).

13C-nmr(CDCl3, 75.5 MHz) δ; 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 41.34, 44.95, 49.77, 56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79.20, 96.32, 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 205.94. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 10.88, 15.56, 16.66, 18.60, 19.17, 21.65, 22.00, 27.37, 28.48, 33.07, 35.50, 37.98, 40.63, 41.34, 44.95, 49.77, 56.22, 65.98, 70.53, 71.01, 74.43, 77.28, 78.67, 79.20, 96.32 107.01, 112.48, 117.66, 120.98, 123.18, 146.82, 150.52, 172.47, 205.94.

실시예 15Example 15

6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심](15)의 제조.6- (4-Dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5-acetoxy -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Preparation of 10- [O- (4-methoxy-phenoxymethyl) -oxime] (15).

화합물 (1)(1.1 g, 1.19 mmol)을 CH2Cl2(10 ml)에 녹이고 아세트산 무수물(0.582 ml, 6.54 mmol)과 I2(50 mg,0.19 mmol)를 한번에 가하고 상온에서 4시간 동안 반응시켰다. 반응 혼합물을 CH2Cl2(10 ml x 3)로 추출한 후, 유기층을 포화 소금물로 세척하고 MgSO4로 건조시켰다. 이 용액을 건조제를 사용한 여과를 수행하고, 여액을 감압 농축시켜 목적화합물을 얻었다.Compound (1) (1.1 g, 1.19 mmol) was dissolved in CH 2 Cl 2 (10 ml), acetic anhydride (0.582 ml, 6.54 mmol) and I 2 (50 mg, 0.19 mmol) were added in one portion, and reacted at room temperature for 4 hours. I was. After the reaction mixture was extracted with CH 2 Cl 2 (10 ml × 3), the organic layer was washed with saturated brine and dried over MgSO 4 . The solution was filtered using a desiccant, and the filtrate was concentrated under reduced pressure to obtain the target compound.

수율 : 1.28 g(98%)Yield: 1.28 g (98%)

1H-NMR(CDCl3, 300 MHz) δ 0.81(t, J=7.29, 3H), 0.90(d, J=7.38 Hz, 3H), 0.96(d, J=6.88 Hz, 3H), 1.13(m, 25H), 2.04(s,3H), 2.21(s, 6H, N(CH3)2), 2.22(s, 9H), 2.51(m, 2H), 3.34(s, 3H), 3.40(d, J=6.85 Hz, 1H), 4.70(dd, J=10.5 Hz, 7.62 Hz, 1H), 4.89(d, J=4.44 Hz, 1H), 5.01(m, 1H), 5.51(dd, J=28.3 Hz, 7.16 Hz, 2H), 6.83(dd, J=38.47 Hz, 9.07 Hz, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.81 (t, J = 7.29, 3H), 0.90 (d, J = 7.38 Hz, 3H), 0.96 (d, J = 6.88 Hz, 3H), 1.13 (m , 25H), 2.04 (s, 3H), 2.21 (s, 6H, N (CH 3 ) 2 ), 2.22 (s, 9H), 2.51 (m, 2H), 3.34 (s, 3H), 3.40 (d, J = 6.85 Hz, 1H), 4.70 (dd, J = 10.5 Hz, 7.62 Hz, 1H), 4.89 (d, J = 4.44 Hz, 1H), 5.01 (m, 1H), 5.51 (dd, J = 28.3 Hz , 7.16 Hz, 2H), 6.83 (dd, J = 38.47 Hz, 9.07 Hz, 4H)

13C-nmr(CDCl3, 75.5 MHz) δ; 9.58, 11.19, 15.09, 16.92, 19.07, 21.75, 22.04, 22.69, 27.35, 27.65, 30.84, 33.77, 356.61, 37.73, 39.25, 41.18, 45.18, 49.90, 56.11, 64.08, 66.11, 68.74, 70.78, 72.20, 73.32, 74.76, 75.42, 77.34, 78.54, 80.33, 83.82, 96.00, 96.63, 101.22, 115.54, 119.02, 150.92, 155,66, 166.96, 170.54, 174.50, 175.52. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 9.58, 11.19, 15.09, 16.92, 19.07, 21.75, 22.04, 22.69, 27.35, 27.65, 30.84, 33.77, 356.61, 37.73, 39.25, 41.18, 45.18, 49.90, 56.11, 64.08, 66.11, 68.74, 70.78, 72.20, 73.32 74.76, 75.42, 77.34, 78.54, 80.33, 83.82, 96.00, 96.63, 101.22, 115.54, 119.02, 150.92, 155,66, 166.96, 170.54, 174.50, 175.52.

실시예 16Example 16

6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심](16)의 제조.6- (4-Dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5-acetoxy -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Preparation of 10- [O- (2-methoxy-phenoxymethyl) -oxime] (16).

실시예 15와 같은 방법으로 제조하였다.It was prepared in the same manner as in Example 15.

수율 : 95 %Yield: 95%

1H-NMR(CDCl3, 300 MHz) δ 1.03(m, 6H), 1.06~1.72(m, 40H), 2.04(s, 3H), 2.22(s, 9H), 2.32(s, 6H, N(CH3)2), 2.58(m, 1H), 2.96(m, 2H), 3.31(s, 3H, 3'-OCH3), 3.60(m, 6H), 3.84(s, 3H, ph-OCH3), 4.25(s, 1H), 4.40(d, J=7.11 Hz, 1H, 1'-H), 4.90(d, J=4.59 Hz, 1H, 1'-H), 5.14(dd ,J=10.73 Hz, 2.28 Hz 1H), 5.64(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 1.03 (m, 6H), 1.06 to 1.72 (m, 40H), 2.04 (s, 3H), 2.22 (s, 9H), 2.32 (s, 6H, N ( CH 3 ) 2 ), 2.58 (m, 1H), 2.96 (m, 2H), 3.31 (s, 3H, 3'-OCH 3 ), 3.60 (m, 6H), 3.84 (s, 3H, ph-OCH 3 ), 4.25 (s, 1H), 4.40 (d, J = 7.11 Hz, 1H, 1'-H), 4.90 (d, J = 4.59 Hz, 1H, 1'-H), 5.14 (dd, J = 10.73 Hz, 2.28 Hz 1H), 5.64 (dd, J = 30,21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H).

실시예 17Example 17

아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(4-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르(17)의 합성.Acetic acid 4-dimethylamino-2- [14-ethyl-4,7,12,13-tetrahydroxy-10- (4-methoxy-phenoxymethoxyimino) -3,5,7,9,11 , 13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl ester (17).

실시예 9와 같은 방법으로 제조하였다.It prepared in the same manner as in Example 9.

수율 :83%Yield: 83%

FAB-MS : M+= 721FAB-MS: M + = 721

1H-NMR(CDCl3, 300 MHz) δ 0.81(t, J=7.38 Hz, 3H), 0.89(d, J=7.47 Hz, 3H), 0.96(d, J=6.99 Hz, 3H), 1.15(m, 22H), 2.07(s, 3H), 2.27(s, 6H, N(CH3)2), 2.64(m, 3H), 2.17(s, 1H), 3.45(m, 2H), 3.78(s, 3H), 4.15(s, 1H), 4.53(d, J=7.65 Hz. 1H), 4.72(dd, J=10.2 Hz, 7.71 Hz, 1H), 5.21(dd, 11.13 Hz, 2.15 Hz,1H), 5.52(dd, J=30.07 Hz, 7.14 Hz, 2H), 6.83(dd, J=25.78 Hz, 9.17 Hz, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.81 (t, J = 7.38 Hz, 3H), 0.89 (d, J = 7.47 Hz, 3H), 0.96 (d, J = 6.99 Hz, 3H), 1.15 ( m, 22H), 2.07 (s, 3H), 2.27 (s, 6H, N (CH 3 ) 2 ), 2.64 (m, 3H), 2.17 (s, 1H), 3.45 (m, 2H), 3.78 (s , 3H), 4.15 (s, 1H), 4.53 (d, J = 7.65 Hz. 1H), 4.72 (dd, J = 10.2 Hz, 7.71 Hz, 1H), 5.21 (dd, 11.13 Hz, 2.15 Hz, 1H) , 5.52 (dd, J = 30.07 Hz, 7.14 Hz, 2H), 6.83 (dd, J = 25.78 Hz, 9.17 Hz, 4H)

13C-nmr(CDCl3, 75.5 MHz) δ; 7.71, 10.51, 14.62, 15.30, 16.43, 18.34, 21.02, 21.36, 21.44, 30.97, 33.29, 36.42, 36.64, 40.62, 43.66, 55.60, 63.16, 68.66, 70.54, 71.35, 74.17, 74.56, 76.56, 76.74, 77.75, 83.78, 95.83, 99.76, 114.71, 118.41, 150.55, 155.05, 169.99, 174.12, 174.27. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 7.71, 10.51, 14.62, 15.30, 16.43, 18.34, 21.02, 21.36, 21.44, 30.97, 33.29, 36.42, 36.64, 40.62, 43.66, 55.60, 63.16, 68.66, 70.54, 71.35, 74.17, 74.56, 76.56, 76.74, 77.75, 77.75 83.78, 95.83, 99.76, 114.71, 118.41, 150.55, 155.05, 169.99, 174.12, 174.27.

실시예 18Example 18

아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(2-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르 (18)의 제조.Acetic acid 4-dimethylamino-2- [14-ethyl-4,7,12,13-tetrahydroxy-10- (2-methoxy-phenoxymethoxyimino) -3,5,7,9,11 , 13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl ester (18).

수율 : 85%Yield: 85%

1H-NMR(CDCl3, 300 MHz) δ 0.83(t, J=7.32 Hz, 3H), 0.90(d, J=7.00 Hz, 3H), 1.05~1.69(m, 22H), 1.91(m, 2H), 2.05(s, 3H) 2.24(s, 6H, N(CH3)2), 2.57(m, 5H), 2.98(s, 1H), 3.30(m, 3H), 3.48(m, 9H), 3.85(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.29(s, 1H), 4.34(d, J=7.11 Hz, 1H, 1'-H), 5.20(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.68(dd, J=30,21 Hz, 7.08 Hz, NO-CH2-O-), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.83 (t, J = 7.32 Hz, 3H), 0.90 (d, J = 7.00 Hz, 3H), 1.05-1.69 (m, 22H), 1.91 (m, 2H ), 2.05 (s, 3H) 2.24 (s, 6H, N (CH 3 ) 2 ), 2.57 (m, 5H), 2.98 (s, 1H), 3.30 (m, 3H), 3.48 (m, 9H), 3.85 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.29 (s, 1H), 4.34 (d, J = 7.11 Hz, 1H, 1'-H), 5.20 (dd, J = 10.73 Hz, 2.28 Hz, 1H), 5.68 (dd, J = 30,21 Hz, 7.08 Hz, NO-CH 2 -O-), 6.85 (m, 4H).

실시예 19Example 19

13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸-3,9-다이온-9-[O-(4-메톡시-페녹시메틸)]-옥심 (19)의 제조.13- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6,8,10 , 12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecan-3,9-dione-9- [O- (4-methoxy-phenoxymethyl)]-oxime (19) Preparation.

실시예 13과 같은 방법으로 제조하였다.It prepared in the same manner as in Example 13.

수율 : 97%Yield: 97%

FAB-MS : M+= 710FAB-MS: M + = 710

1H-NMR(CDCl3, 300 MHz) δ 0.85(t, J=7.25 Hz, 3H), 0.98(d, J=6.37 Hz, 3H), 1.07(m, 24H), 1.67(m, 3H), 2.29(s, 6H, N(CH3)2), 2.51(m, 1H), 2.62(m, 2H), 3.24(m, 1H), 3.49(m, 3H), 3.66(d, J=4.52 Hz, 1H), 3.73(s, 3H), 3.95(m, 1H), 4.19(d, J=7.20 Hz, 1H), 4.34(bs, 1H), 5.01(d, J=10.54 Hz, 1H), 5.53(dd, J=16.89 Hz, 7.54 Hz, 2H), 6.82(dd, J=36.19 Hz, 8.82 Hz, 4H) 1 H-NMR (CDCl 3 , 300 MHz) δ 0.85 (t, J = 7.25 Hz, 3H), 0.98 (d, J = 6.37 Hz, 3H), 1.07 (m, 24H), 1.67 (m, 3H), 2.29 (s, 6H, N (CH 3 ) 2 ), 2.51 (m, 1H), 2.62 (m, 2H), 3.24 (m, 1H), 3.49 (m, 3H), 3.66 (d, J = 4.52 Hz , 1H), 3.73 (s, 3H), 3.95 (m, 1H), 4.19 (d, J = 7.20 Hz, 1H), 4.34 (bs, 1H), 5.01 (d, J = 10.54 Hz, 1H), 5.53 (dd, J = 16.89 Hz, 7.54 Hz, 2H), 6.82 (dd, J = 36.19 Hz, 8.82 Hz, 4H)

13C-nmr(CDCl3, 75.5 MHz) δ; 11.28, 13.99, 16.92, 20.06, 21.16, 21.78, 25.39, 28.87, 29.09, 40.90, 50.20, 50.62, 56.11, 66.08, 70.07, 70.23, 78.46, 84.58, 94.92, 96.33, 115.04, 118.97, 151.68, 155.42, 172.39, 177.35. 13 C-nmr (CDCl 3 , 75.5 MHz) δ; 11.28, 13.99, 16.92, 20.06, 21.16, 21.78, 25.39, 28.87, 29.09, 40.90, 50.20, 50.62, 56.11, 66.08, 70.07, 70.23, 78.46, 84.58, 94.92, 96.33, 115.04, 118.97, 151.68, 15392, 15392, 177.35.

실시예 20Example 20

13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸-3,9-다이온-9-[O-(2-메톡시-페녹시메틸)-옥심] (20)의 제조.13- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6,8,10 , 12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecan-3,9-dione-9- [O- (2-methoxy-phenoxymethyl) -oxime] Preparation of 20.

수율 : 96%Yield: 96%

1H-NMR(CDCl3, 300 MHz) δ 0.83(t, J=7.21 Hz, 3H), 0.90(d, J=7.00 Hz, 3H), 1.05~1.69(m, 24H), 1.91(m, 2H), 2.24(s, 6H, N(CH3)2), 2.57(m, 5H), 2.98(s, 1H), 3.30(m, 3H), 3.48(m, 9H), 3.85(s, 3H, ph-OCH3), 3.82(bs, 1H), 4.29(s, 1H), 4.34(d, J=7.11 Hz, 1H, 1'-H), 5.20(dd, J=10.73 Hz, 2.28 Hz, 1H), 5.68,(dd, J=30,21 Hz, 7.08 Hz), 6.85(m, 4H). 1 H-NMR (CDCl 3 , 300 MHz) δ 0.83 (t, J = 7.21 Hz, 3H), 0.90 (d, J = 7.00 Hz, 3H), 1.05 to 1.69 (m, 24H), 1.91 (m, 2H ), 2.24 (s, 6H, N (CH 3 ) 2 ), 2.57 (m, 5H), 2.98 (s, 1H), 3.30 (m, 3H), 3.48 (m, 9H), 3.85 (s, 3H, ph-OCH 3 ), 3.82 (bs, 1H), 4.29 (s, 1H), 4.34 (d, J = 7.11 Hz, 1H, 1'-H), 5.20 (dd, J = 10.73 Hz, 2.28 Hz, 1H ), 5.68, (dd, J = 30, 21 Hz, 7.08 Hz), 6.85 (m, 4H).

에리스로마이신 A로부터 제조된 본 발명의 신규 마크로라이드화합물 또는 그의 약리학적 허용되는 염은 여러 위장질환, 예를들면, 만성위염, 위궤양, 십이지장궤양, 위암발생에 있어 중요한 원인균으로 알려진 헬리코박터 파이로리(Helicobactoer pylori)의 성장 저해효과가 매우 우수하였다. 또한 다른 공지의 에리트로마이신 유도체에 비하여 위산에 대한 분해정도가 현저하게 낮게 나타났다. 따라서 본 발명의 화합물은 우리나라의 성인 남녀에 있어 헤리코박터 파이로리(Helicobactoer pylori)의 보균률이 매우 높은 점을 고려해 볼 때 헤리코박터 파이로리(Helicobactoer pylori)에 제균력을 나타내는 점과 해당 화합물들이 항 궤양제로서 유용하게 사용될 것으로 기대된다.Erythromycin salt of a novel macrolide compound or allow its pharmacologically of the present invention prepared from A are several gastrointestinal diseases, for example, in chronic gastritis, gastric ulcer, duodenal ulcer, gastric cancer is known as an important pathogen Helicobacter pylori (Helicobactoer pylori ) Showed very good growth inhibition effect. In addition, the degree of degradation of gastric acid was significantly lower than that of other known erythromycin derivatives. Therefore, the compounds of the present invention, considering the very high carrier rate of Helicobactoer pylori in adult men and women in Korea, the point that the antimicrobial power to Helicobactoer pylori and the compounds are antibacterial It is expected to be useful as an ulcer agent.

Claims (4)

화학식 1의 화합물:Compound of Formula 1: [화학식 1][Formula 1] 상기 화학식 1에서, R1은 4-메톡시페녹시메틸기, 2-메톡시페녹시메틸기 또는 메톡시에톡시메틸기를 나타내고; R2는 수소원자, 아실기, 또는 저급알콕시기를 나타내고; R3는 수소원자 또는 아실기이고 각각은 모두 같거나 다르며; Q와 W는 함께 옥소를 형성하거나, Q 및 W 중 하나는 -OR4이고 다른 하나는 수소이고, R4는 수소원자 또는이며, 여기서 R3의 정의는 전술한 바와 같다.In Formula 1, R 1 represents a 4-methoxyphenoxymethyl group, 2-methoxyphenoxymethyl group, or methoxyethoxymethyl group; R 2 represents a hydrogen atom, an acyl group, or a lower alkoxy group; R 3 is a hydrogen atom or an acyl group and each is the same or different; Q and W together form oxo, or one of Q and W is -OR 4 and the other is hydrogen, and R 4 is a hydrogen atom or Wherein R 3 is as defined above. 제1항에 있어서,The method of claim 1, 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-트리메틸실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-트리메틸실릴-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-트리히드록시-4-(5-트리메텔실릴-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7-메톡시-12,13-다이히드록시-4-(5-히드록시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(4-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르, 아세트산 4-다이메틸아미노-2-[14-에틸-4,12,12-트리히드록시-7-메톡시-10(2-메톡시페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일-에스테르, 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-4,12,13-트리히드록시-7-메톡시-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,4,10-트리온10-[O-(2-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(4-메톡시-페녹시메틸)-옥심], 6-(4-다이메틸아미노-3-아세톡시-6-메틸-테트라히드로-피란-2-일옥시)-14-에틸-7,12,13-트리아세톡시-4-(5-아세톡시-4-메톡시-4,6-다이메틸-테트라히드로-피란-2-일옥시)-3,5,7,9,11,13-헥사메틸-옥사시클로테트라데칸-2,10-다이온10-[O-(2-메톡시-페녹시메틸)-옥심], 아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(4-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르, 아세트산 4-다이메틸아미노-2-[14-에틸-4,7,12,13-테트라히드록시-10-(2-메톡시-페녹시메톡시이미노)-3,5,7,9,11,13-헥사메틸-2-옥소-옥사시클로테트라덱-6-일옥시]-6-메틸-테트라히드로-피란-3-일 에스테르, 13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸-3,9-다이온-9-[O-(4-메톡시-페녹시메틸)]-옥심 및 13-(4-다이메틸아미노-3-히드록시-6-메틸-테트라히드로-피란-2-일옥시)-5-에틸-1,6,7-트리히드록시-2,6,8,10,12-펜타메틸-14,15-다이옥사-바이시클로[10,2,1]펜타데칸-3,9-다이온-9-[O-(2-메톡시-페녹시메틸)-옥심]으로 구성되는 군에서 선택되는 화합물6- (4-Dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-hydroxy -4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14- Ethyl-7,12,13-trihydroxy-4- (5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9 , 11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-trimethyl Silyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-trimethylsilyl-4-methoxy-4,6-dimethyl -Tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10- [O- (4-methoxy-phenoxy Dimethyl) -oxime] , 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-trihydroxy-4- (5-tri Methylsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10- Dione 10- [O- (2-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy)- 14-ethyl-7-methoxy-12,13-dihydroxy-4- (5-trimethylsilyl-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3, 5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime], 6- (4-dimethyl Amino-3-trimethylsilyl-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-trihydroxy-4- (5-trimethylsilyl-4- Methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-di On 10- [O- (2-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14 -Ethyl-7-methoxy-12,13-dihydroxy-4- (5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5 , 7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino -3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7-methoxy-12,13-dihydroxy-4- (5-hydroxy-4-methoxy -4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12 , 13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (4-methoxy-phenoxy Dimethyl) -oxime], 6- (4-dime Amino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11 , 13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime], 4-dimethylamino-2- [14-ethyl- 4,12,12-Trihydroxy-7-methoxy-10 (4-methoxyphenoxymethoxyimino) -3,5,7,9,11,13-hexamethyl-2-oxo-oxacyclotetra Dec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl-ester, 4-dimethylamino-2- [14-ethyl-4,12,12-trihydroxy-7-meth Toxy-10 (2-methoxyphenoxymethoxyimino) -3,5,7,9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetra Hydro-pyran-3-yl-ester, 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-tri Hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (4-methoxy- Phenoxymethyl) -oxime], 6- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-4,12,13-trihydroxy -7-methoxy-3,5,7,9,11,13-hexamethyl-oxacyclotetedecane-2,4,10-trione 10- [O- (2-methoxy-phenoxymethyl)- Oxime], 6- (4-dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5 Acetoxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10 -Dione 10- [O- (4-methoxy-phenoxymethyl) -oxime], 6- (4-dimethylamino-3-acetoxy-6-methyl-tetrahydro-pyran-2-yloxy) -14-ethyl-7,12,13-triacetoxy-4- (5-acetoxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy) -3,5, 7,9,11,13-hexamethyl-oxacyclotetedecane-2,10-dione 10- [O- (2-methoxy-phenoxymethyl) -oxime], 4-dimethylamino-2-acetic acid [14-ethyl-4,7,12 , 13-tetrahydroxy-10- (4-methoxy-phenoxymethoxyimino) -3,5,7,9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy ] -6-methyl-tetrahydro-pyran-3-yl ester, acetic acid 4-dimethylamino-2- [14-ethyl-4,7,12,13-tetrahydroxy-10- (2-methoxy- Phenoxymethoxyimino) -3,5,7,9,11,13-hexamethyl-2-oxo-oxacyclotetradec-6-yloxy] -6-methyl-tetrahydro-pyran-3-yl ester , 13- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6,8, 10,12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecan-3,9-dione-9- [O- (4-methoxy-phenoxymethyl)]- Oxime and 13- (4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy) -5-ethyl-1,6,7-trihydroxy-2,6,8 , 10,12-pentamethyl-14,15-dioxa-bicyclo [10,2,1] pentadecane-3,9-dione-9- [O- (2-methoxy-phenoxymethyl)- Oxime] Compound selected from the group 제1항의 화합물을 유효성분으로 함유하는 헬리코박터 파이로리의 성장을 저해하는 조성물.A composition that inhibits the growth of Helicobacter pylori containing the compound of claim 1 as an active ingredient. 제2항의 화합물을 유효성분으로 함유하는 헬리코박터 파이로리의 성장을 저해하는 조성물.A composition that inhibits the growth of Helicobacter pylori containing the compound of claim 2 as an active ingredient.
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JPH03204893A (en) * 1989-10-07 1991-09-06 Taisho Pharmaceut Co Ltd 6-o-methylerythromycin a oxime derivative
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